The study of the biochemical events involved in the activation of guinea pig macrophages and the subsequent production of collagenase have demonstrated a role for ornithine decarboxylase (ODC) and the polyamines generated by this enzyme in the regulation of collagenase production. This has been confirmed by the ability of difluoromethyl ornithine, a specific inhibitor of ODC, to block collagenase and by the restoration of collagenase production by the polyamine putrescine. ODC activity was also shown to regulated by PGE2 since indomethacin reduced the levels of this enzyme. When human monocytes, purified by counterflow centrifugal elutriation, were activated in vitro they produced collagenase. Cycloheximide blocked collagenase production indicating that protein synthesis was required. Indomethacin inhibited stimulable monocyte collagenase only if no detectable enzyme was found in control cultures. However, when collagenase was detected in control cultures, indicating previous activation, indomethacin had no effect. Studies on the regulation of the immune system with prostaglandins and the subsequent effect on connective tissue metabolism have been extended to the examination of all the arachidonic acid (AA) metabolites. This has resulted in the detection of greater amounts of 5-hydroxy-eicosatetranoic acid (5-HETE) produced by the spleen cells of osteopetrotic rats (toothless [tl] rats) when compared with those of normal littermates. The potential effect of 5-HETE on the immune system and bone resorption is being investigated.